Chronic inhibition of fatty acid oxidation: new model of diastolic dysfunction

Abstract

This study was designed to determine the changes in the heart that result from inhibition of long-chain fatty acid oxidation with 2-tetradecylglycidic acid (TDGA). Male Sprague-Dawley rats (n = 64) were treated with TDGA (20 mg.kg-1.day-1) or a comparable volume of vehicle by gavage feeding for 7 or 21 days. In conscious rats TDGA produced no changes in heart rate, left ventricular systolic or end-diastolic pressures, left ventricular pressure development (dP/dt), or the time constant of left ventricular relaxation. Left ventricular developed pressure was not changed at 21 days. TDGA increased left ventricular weight, left ventricular weight-to-body weight ratio, and total heart weight-to-body weight ratio. Left ventricular endocardial and epicardial myocyte volumes were increased by 53 and 65%, respectively. Myocardial triglyceride content was increased threefold. Left ventricular chamber stiffness constants between end-diastolic pressures of 0 and 30 mmHg were increased, and left ventricular end-diastolic volumes at operating end-diastolic pressures were decreased at both 7 and 21 days. The myocardial stiffness constant was also increased at 7 and 21 days. Thus inhibition of long-chain fatty acid oxidation with TDGA increased left ventricular mass and altered left ventricular chamber and muscle stiffness without changing left ventricular relaxation or systolic function. We conclude that inhibition of long-chain fatty acid oxidation produced an unusual model of left ventricular hypertrophy and diastolic dysfunction characterized by abnormalities of passive-elastic properties but preserved relaxation.

L-Carnitine Supplementation Decreases the Left Ventricular Mass in Patients Undergoing Hemodialysis

“…26 Litwin et al reported that administration of TDGA induced LVH with storage of lipids in rat hearts. 27 These results indicate that, in patients undergoing HD, carnitine deficiency disturbs myocardial fatty acid metabolism and may induce myocardial lipid accumulation. Therefore, some removal of lipid storage from myocardial cytoplasm might play an additional role in decreasing LVM.…”

Peroxisome Proliferator–Activated Receptor α Gene Regulates Left Ventricular Growth in Response to Exercise and Hypertension

“…There is a growing body of evidence that appropriate substrate use is critical for cardiac function. Defects in FAO enzymes cause childhood cardiomyopathies, 9 and pharmacological inhibition of cardiac FA import induces cardiac hypertrophy 26 and causes rapid death in PPAR␣-knockout mice. 20 Transgenic mice that overexpress long-chain acyl-CoA synthetase and take up excess long chain fatty acids initially exhibit cardiac hypertrophy, followed by LV dysfunction and death.…”

Threshold effects of glucose transporter-4 (GLUT4) deficiency on cardiac glucose uptake and development of hypertrophy

“…Although there may be several different mechanisms for these diabetes-related cardiac abnormalities, one possibility is a reduction in glucose availability secondarily to a marked reduction in the insulinresponsive glucose transporter (GLUT4) expression (Garvey et al 1993). Consistent with the deficiency of energy substrates as the cause of cardiac abnormalities, is the fact that inhibition of free fatty acid oxidation, the heart's major energy source, results in cardiac enlargement (Litwin et al 1990b).…”

“…Rats in which mitochondrial free fatty acid oxidation is inhibited with the carnitine palmitoyl transferase-1 inhibitor, 2-tetradecylglycidic acid, develop cardiac hypertrophy in the absence of changes in blood pressure (Litwin et al 1990b, Bressler & Goldman 1993. Although the heart preferentially metabolises fat, human studies have shown that glucose metabolism becomes important when there are high energy needs such as with exercise (Gertz et al 1988).…”